Reactive oxygen species (ROS) play an important role in normal cellular physiology. They regulate different biologic processes such as cell defense, hormone synthesis and signaling, activation of G protein-coupled receptors, and ion channels and kinases/phosphatases. ROS are also important regulators of transcription factors and gene expression. On the other hand, in pathologic conditions, a surplus of ROS in tissue results in oxidative stress with various injurious consequences such as inflammation and fibrosis. NADPH oxidases are one of the many sources of ROS in biologic systems, and there are seven isoforms (Nox1-5, Duox1, Duox2). Nox4 is the predominant form in the kidney, although Nox2 is also expressed. Nox4 has been implicated in the basal production of ROS in the kidney and in pathologic conditions such as diabetic nephropathy and CKD; upregulation of Nox4 may be important in renal oxidative stress and kidney injury. Although there is growing evidence indicating the involvement of NADPH oxidase in renal pathology, there is a paucity of information on the role of NADPH oxidase in the regulation of normal renal function. Here we provide an update on the role of NADPH oxidases and ROS in renal physiology and pathology.

OBJECTIVE-Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR).RESEARCH DESIGN AND METHODS-Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR Ն135 ml/min per 1.73 m 2 ), and 12 subjects exhibited normofiltration (GFR Ͻ135 ml/min per 1.73 m 2 ).RESULTS-Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 Ϯ 5 to 139 Ϯ 5 ml/min per 1.73 m 2 ) but increased GFR in the normofiltration group (118 Ϯ 5 to 138 Ϯ 5 ml/min per 1.73 m 2 ). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR.CONCLUSIONS-In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states. Diabetes 57: 688-695, 2008 A lterations in renal hemodynamic function are prevalent in diabetes (1,2) and include increased intraglomerular capillary pressure and hyperfiltration (3-5). Because blockade of the renin angiotensin system (RAS) does not completely normalize hyperfiltration (6), it is clear that other factors are operative in the renal microcirculation in diabetes.Animal studies have examined the role of vasodilatation (7) in the pathogenesis of hyperfiltration. Early work focused on the role of cyclooxygenase (COX)-derived prostanoids, which exert a variety of functions in the kidney, including important vasodilatory effects; however, studies initially used nonspecific COX1/COX2 inhibitors (8). With the discovery of the COX2 isoform and selective COX2 inhibitors, experimental models of diabetes revealed that COX2 expression is increased in the macula densa in this condition and is associated with enhanced production of vasodilatory prostaglandins, RAS activation, and renal hyperfiltration (9). Moreover, in streptozotocininduced diabetic rat models with a renal hyperfiltration phenotype, hyperglycemia-associated prostaglandin production and hyperfiltration were blunted using COX2 inhibition (9). Given the association between renal hyperfiltration, intraglomerular hypertension, and nephropathy related to diabetes (7,10,11), the elucidation of COX2-mediated renal hemodynamic function changes in dia...

(DM) suggest that increased nitric oxide (NO) bioactivity contributes to renal hyperfiltration. However, the role of NO in mediating hyperfiltration has not been fully elucidated in humans. Our aim was to examine the effect of NO synthase inhibition on renal and peripheral vascular function in normotensive subjects with uncomplicated type 1 DM. Renal function and brachial artery flow-mediated vasodilatation (FMD) were measured before and after an intravenous infusion of the NO synthase inhibitor N G -nitro-Larginine methyl ester (L-NMMA) in 21 healthy control and 37 type 1 DM patients. Measurements in DM participants were made under clamped euglycemic conditions. The effect of L-NMMA on circulating and urinary NO metabolites (NOx) and cGMP and on urinary prostanoids was also determined. Baseline characteristics were similar in the two groups. For analysis, the DM patients were divided into those with hyperfiltration (DM-H, n ϭ 18) and normal glomerular filtration rate (GFR) levels (DM-N, n ϭ 19). Baseline urine NOx and cGMP were highest in DM-H. L-NMMA led to a decline in GFR in DM-H (152 Ϯ 16 to 140 Ϯ 11 ml·min Ϫ1 ·1.73 m Ϫ2 ) but not DM-N or healthy control participants. The decline in effective renal plasma flow in response to L-NMMA (806 Ϯ 112 to 539 Ϯ 80 ml·min Ϫ1 ·1.73 m Ϫ2 ) in DM-H was also exaggerated compared with the other groups (repeated measures ANOVA, P Ͻ 0.05), along with declines in urinary NOx metabolites and cGMP. Baseline FMD was lowest in DM-H compared with the other groups and did not change in response to L-NMMA. L-NMMA reduced FMD and plasma markers of NO bioactivity in the healthy control and DM-N groups. In patients with uncomplicated type 1 DM, renal hyperfiltration is associated with increased NO bioactivity in the kidney and reduced NO bioactivity in the systemic circulation, suggesting a paradoxical state of high renal and low systemic vascular NO bioactivity. endothelial function; hyperfiltration; nitric oxide; type 1 diabetes GLOMERULAR HYPERFILTRATION is an early renal hemodynamic change in animal and human studies of diabetes mellitus (DM) and may help to predict the risk for the subsequent development of diabetic nephropathy (38). The pathogenesis of hyperfiltration is complex and involves both tubuloglomerular feedback and hemodynamic abnormalities. Renal hemodynamic changes associated with hyperfiltration include afferent vasodilatation and efferent constriction. Hyperfiltration is, however, only partially corrected after selective cyclooxygenase-2 inhibition (predominant afferent constriction) or renin angiotensin system (RAS) blockade (predominant efferent vasodilatation) in humans with uncomplicated type 1 DM (8, 54). These findings suggest the presence of nonprostaglandin, non-RAS-dependent hemodynamic mechanisms that perpetuate the hyperfiltration state (60).Functional expression studies in DM models have determined that endothelial nitric oxide (NO) synthase (eNOS) expression is consistently upregulated and localized to the afferent arteriole, renal cortex, and medull...

Chronic kidney disease is a leading cause of morbidity and mortality in the world. A better understanding of disease mechanisms has been gained in recent years, but the current management strategies are ineffective at preventing disease progression. A widespread focus of research is placed on elucidating the specific processes implicated to find more effective therapeutic options. PGE2, acting on its four EP receptors, regulates many renal disease processes; thus EP receptors could prove to be important targets for kidney disease intervention strategies. This review summarizes the major pathogenic mechanisms contributing to initiation and progression of chronic kidney disease, emphasizing the role of hyperglycemia, hypertension, inflammation, and oxidative stress. We have long recognized the multifaceted role of PGs in both the initiation and progression of chronic kidney disease, yet studies are only now seriously contemplating specific EP receptors as targets for therapy. Given the plethora of renal complications attributed to PG involvement in the kidney, this review highlights these pathogenic events and emphasizes the PGE2 receptor targets as options available to complement current therapeutic strategies.